Biology subjects

Hayes, D. N.

Publications and source records attributed to Hayes, D. N..

2 recordsLinked to original sources

bioRxiv2021

Systematic analysis of SARS-CoV-2 infection of an ACE2-negative human airway cell

Established in vitro models for SARS-CoV-2 infection are limited and include cell lines of non-human origin and those engineered to overexpress ACE2, the cognate host cell receptor. We identified human H522 lung adenocarcinoma cells as naturally permissive to SARS-CoV-2 infection despite complete absence of ACE2. Infection of H522 cells required the SARS-CoV-2 spike protein, though in contrast to ACE2-dependent models, spike alone was not sufficient for H522 infection. Temporally resolved transcriptomic and proteomic profiling revealed alterations in cell cycle and the antiviral host cell response, including MDA5-dependent activation of type-I interferon signaling. Focused chemical screens point to important roles for clathrin-mediated endocytosis and endosomal cathepsins in SARS-CoV-2 infection of H522 cells. These findings imply the utilization of an alternative SARS-CoV-2 host cell receptor which may impact tropism of SARS-CoV-2 and consequently human disease pathogenesis.

microbiology↗

bioRxiv2020

CRTC1-MAML2 Establishes a PGC1α-IGF1 Circuit that Confers Vulnerability to PPARγ Inhibition

Mucoepidermoid carcinoma (MEC) is a life-threatening salivary gland cancer that is driven primarily by the transcriptional co-activator fusion CRTC1-MAML2. The mechanisms by which the chimeric CRTC1-MAML2 oncoprotein rewires gene expression programs that promote tumorigenesis remain poorly understood. Here, we show that CRTC1-MAML2 induces transcriptional activation of the non-canonical PGC-1 splice variant PGC-14, which regulates PPAR{gamma}-dependent IGF-1 expression. This mitogenic transcriptional circuitry is consistent across cell lines and primary tumors. CRTC1-MAML2 positive tumors are dominated by IGF-1 pathway activation and small molecule drug screens reveal that tumor cells harboring the fusion gene are selectively sensitive to IGF-1R inhibition. Furthermore, this dependence on autocrine regulation of IGF-1 transcription renders MEC cells susceptible to PPAR{gamma}inhibition with inverse agonists. These results yield insights into the aberrant co-regulatory functions of CRTC1-MAML2 and identify a specific vulnerability that can be exploited for precision therapy.

cancer biology↗